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i
A South African Case Study Of Familial Membranoproliferative Glomerulonephritis
Claudia Lewis Do Vale
A research report submitted to the Faculty of Health Sciences, University of the
Witwatersrand, in partial fulfilment for the degree of Masters of Medicine
Johannesburg 2015
i
Candidate’s Declaration
I, Claudia Lewis Do Vale declare that this research report is my own work. It is being
submitted for the degree of Masters in Medicine in the University of the
Witwatersrand, Johannesburg. It has not been submitted before for any degree or
examination at this or any other University.
……………………..
The 30th day of January 2015
ii
Abstract
Membranoproliferative glomerulonephritis (MPGN) is an immune-mediated disease that is
characterised by mesangial hypercellularity and endocapilliary proliferation with capillary
wall remodeling which results in thickening of the glomerular basement membrane. (1)
MPGN was traditionally classified on electron microscopy findings into MPGN type I, II,
and III. Multiple genetic risk factors have been identified for MPGN II now referred to as
dense deposit disease; however, relatively little is known regarding genetic risk factors for
MPGN type I and III.
A reclassification scheme that better reflects the pathophysiology of MPGN has been
implemented. This scheme divides MPGN into immune-complex-mediated and
complement-mediated MPGN. Previous descriptions of familial MPGN suggest that this
entity falls within the category of complement-mediated MPGN.
We describe a South African family with four family members affected with immune-
complex-mediated MPGN. All other asymptomatic contactable family members were
tested for proteinuria and haematuria and a pedigree for the family was established with an
autosomal recessive with incomplete penetrance inheritance pattern or a multigenic
inheritance pattern.
A systematic review was then performed using the search terms of "inherited MPGN" and
"Familial MPGN". In the systematic review of familial MPGN from 1981-2014, nine
reports containing twelve families were reviewed totaling thirteen families including the
South African family. Six families were found to have immune-complex-mediated MPGN
iii
and five families had complement-mediated MPGN. The data of two families was limited
and thus couldn’t be reclassified.
Most of the family members presented with nephrotic syndrome; and more family
members in the complement-mediated MPGN group (41%) had a decreased serum
complement versus 14% in the immune-complex-mediated group. The mean age of
diagnosis, of the family members in the immune-complex-mediated group was 15 years of
age with a mean age at end stage renal disease of 20 years of age. The mean age of
diagnosis in the complement-mediated group was also 15 years of age with a mean age at
end stage renal disease of 25 years of age. Inheritance patterns varied greatly between the
studies with no clear inheritance pattern being established.
In a previous family studied, a link was found between chromosome 1q, a locus containing
genes for factors affecting the complement cascade. (4) However the systematic review
shows that this family falls under the reclassification of complement-mediated MPGN.
Thus it is unknown if chromosome 1q is also involved in the pathogenesis of inherited
immune-complex-mediated MPGN.
By describing this South African family with familial MPGN and the systematic review of
familial MPGN case studies, we demonstrate that familial MPGN occurs through immune-
complex-mediated and complement-mediated pathways. Based on our findings, the current
classification of MPGN should be modified to include familial immune-complex-mediated
MPGN as a fourth category under immune-complex-mediated MPGN. Further studies are
required to assess the inheritance patterns as well as the underlying genetic abnormality
related to immune-complex-mediated MPGN.
iv
Acknowledgements
I would like to thank Professor S. Naicker, Dr R. Duarte, Dr C. Lippincott, Dr I Do Vale,
Dr C. Profyris, Mr and Mrs M. Do Vale and especially Mr F. Cremona, for all their
assistance and support while completing my research report.
Lastly my gratitude is given to all the family members that consented to be involved in this
study.
v
TABLE OF CONTENTS
Candidate’s Declaration ...................................................................................................... i
Abstract ................................................................................................................................ ii
Acknowledgements ............................................................................................................. iv
TABLE OF CONTENTS .................................................................................................... v
LIST OF FIGURES ............................................................................................................ vi
LIST OF TABLES ............................................................................................................. vii
ABBREVIATIONS ........................................................................................................... viii
INTRODUCTION ............................................................................................................... 1
LITERATURE REVIEW ................................................................................................... 3
AIMS ................................................................................................................................... 30
OBJECTIVES .................................................................................................................... 31
METHODS ......................................................................................................................... 32
RESULTS ........................................................................................................................... 35
DISCUSSION ..................................................................................................................... 58
CONCLUSIONS ................................................................................................................ 61
REFERENCES .................................................................................................................. 62
vi
LIST OF FIGURES
Figure 1: Normal glomerular capillary wall and immune complex mediated MPGN
Figure 2: MPGN findings on light, immunofluorescence and electron microscopy.
Figure 3: Complement mediated MPGN
Figure 4: Pedigree of M family Berry et al.
Figure 5: Pedigree of G family Berry et al.
Figure 6: Pedigree of family Stutchfield et al.
Figure 7: Pedigree of family Sherwood et al.
Figure 8: Pedigree of G family Bakkalogu et al.
Figure 9: Pedigree of family Abderrahim et al.
Figure 10: Pedigree of family Bogdanovic et al.
Figure 11: Pedigree of family Motoyama et al.
Figure 12: Pedigree of family Neary et al.
Figure 13: Pedigree of family 1 Redahan et al.
Figure 14: Pedigree of family 2 Redahan et al.
Figure 15: Pedigree of South African family
vii
LIST OF TABLES
Table 1: Demographics and clinical data
Table 2: Laboratory data
Table 3: Renal biopsy features and MPGN classification
Table 4: Demographics of all families
Table 5: Clinical presentation of all families
Table 6: Laboratory data of all families
Table 7: Biopsy results of all families
Table 8: Immune complex mediated MPGN demographics
Table 9: IM Clinical presentation and residual findings
Table 10: IM laboratory data
Table 11: IM age at ESRD and inheritance pattern
Table 12: CM Demographics
Table 13: CM Clinical presentation and residual findings
Table 14: CM laboratory data
Table 15: CM age at ESRD and inheritance pattern
viii
ABBREVIATIONS
CMJAH: Charlotte Maxeke Johannesburg Academic Hospital
MPGN: Membranoproliferative glomerulonephritis
DDD: Dense deposit disease
IM: Immune complex mediated
CM: Complement mediated
EM: Electron microscopy
LM: Light microscopy
IFM: Immunofluorescence microscopy
MAC: Membrane attack complex
ESRD: End stage renal disease
1
INTRODUCTION
Membranoproliferative glomerulonephritis (MPGN) is an immune mediated
glomerulonephritis that is characterised histopathologically by mesangial hypercellularity,
endocapilliary proliferation with capillary wall remodelling which results in thickening of
the glomerular basement membrane. (1) It is often a chronic, progressive renal disease with
a variable clinical presentation, usually that of an acute nephrotic or nephritic syndrome.
(2) While MPGN was traditionally classified on electro-microscopy findings into MPGN
type I, MPGN type II and MPGN type III, (1) the term MPGN type II was discarded for
the inclusive name of dense deposit disease (DDD). (3) Multiple genetic risk factors have
been identified for DDD (3), while relatively little is known about the underlying genetic
risk factors for MPGN type I and type III, hence this study will focus on familial MPGN
type I and III.
There is a familial incidence of 2.6- 4% of MPGN type I and type III (5) with multiple
patterns of inheritance being considered, the commonest being that of an autosomal
dominant or x-linked pattern of inheritance. (6,7) A familial form of MPGN type III has
been identified with an autosomal dominant pattern of inheritance and it is genetically
linked to band 1q31-32. (4) It has also been suggested that the gene and its function,
predisposing to MPGN, may be modified by other genes that control the immune response,
and hence the difference in the modes of disease expression. (7)
With recent advances in the understanding of the pathophysiology underlying the
formation of MPGN, a reclassification scheme has been recommended to divide MPGN
2
into immune-complex-mediated MPGN and complement mediated MPGN. With this
change in definition the previous descriptions of familial MPGN should also change,
however due to the limited number of reported cases of familial MPGN, little is known
about the epidemiology as well as the progression of disease. By describing the clinical
and pathological features of a South African family with familial MPGN type I, as well as
reviewing reported cases of familial MPGN between 1981 and 2014, an attempt was made
at classifying familial MPGN within the new definitions, as well as reviewing the
epidemiology and disease progression and lastly, further evidence is provided for the
genetic basis underlying this genetic disease.
3
LITERATURE REVIEW
4
Idiopathic membranoproliferative glomerulonephritis (MPGN) is an immune mediated
glomerulonephritis that is chronic and often progressive. It is characterised
histopathologically by mesangial cell hypercellularity and endocapilliary proliferation with
capillary wall remodelling which results in thickening of the glomerular basement
membrane. MPGN commonly presents in childhood and the clinical presentation and
disease course is variable, mainly due to differences in the pathogenesis of the disease. (1)
Traditionally MPGN was classified on electron-microscopy findings into three types
MPGN type I; MPGN type II; MPGN type III. (1) MPGN type II (DDD) was identified as
separate distinct disease entity and MPGN type III was considered a variant of MPGN type
I. (6) Due to recent advances in the understanding of the pathophysiology underlying the
pathogenesis of MPGN, a reclassification scheme has been recommended to divide MPGN
into immune-complex-mediated MPGN and complement-mediated MPGN based on the
underlying pathophysiology. (1)
The pathophysiology of both immune-complex mediated MPGN and complement
mediated MPGN revolves around the complement system. The complement cascade can
be initiated via three pathways, namely the alternative, classical and lectin pathways. (1)
All three pathways meet at the nodal point of the pathway, namely C3, to create the
enzyme complex C3 convertase.
This complex then splits C3 into C3a and C3b. C3b under factor B and D combines with
C3 convertase forming more C3 convertase resulting in an amplification loop. The
association of C3 convertase with C3b also generates C5 convertase which cleaves C5 into
C5a and C5b, which activates the terminal complement complex pathway which forms, via
5
C5b-C9, the membrane-attack complex (MAC) on cell surfaces finally resulting in cell
lysis of the mesangium and capillary walls, known as the injury phase. (1)
The injury phase is accompanied by an inflammatory or proliferative phase with an influx
of inflammatory cells and the release of proteases and cytokines resulting in proteinuria
and haematuria. Ultimately loss of fenestration occurs in the endothelial cells and the
glomerular basement membrane becomes disrupted with effacement of the foot processes
on podocytes.
During the reparative phase, mesangial expansion occurs due to the formation of new
mesangial matrix along with the formation of a new basement membrane, which results in
immune complexes, complement factors, cellular elements, and matrix material being
trapped within the two basement membranes, resulting in the double contours seen along
the capillary walls.
6
Figure 1: Normal Glomerular Capillary Wall and Immune-Complex MPGN.
Panel A is a schematic diagram of the normal glomerular capillary wall and glomerular basement
membrane.
Panel B is a schematic diagram of Immune-Complex MPGN caused via activation of the classical
pathway. The injury phase results from the deposition of immune complexes and complement factors
of the classical and terminal pathways, followed by an influx of leukocytes, leading to a proliferative
phase, with the release of cytokines and proteases (labeled P) resulting in damage to the capillary
walls. Loss of fenestration occurs in the endothelial cells along with disruption of the glomerular
basement membrane with the effacement of the podocyte foot processers. With repair a new basement
membrane is formed, trapping immune complexes, complement factors, cellular elements, and matrix
material within the two basement membranes, resulting in double contours seen along the capillary
walls
Yellow oval structures indicate complement factors. The term sMAC denotes soluble membrane-
attack complex.
Reproduced with permission from Sethi S, Fervenza FC. N Engl J Med 2012;366:1119-1131,
Copyright Massachusetts Medical Society.
7
Thus the pathological feature found on light microscopy (LM) is the appearance of tram
tracks or double contours of the basement membrane, while typically electron microscopy
(EM) reveals mesangial and subendothelial deposits and occasionally intramembranous
and subepithelial deposits. EM shows the replacement of the glomerular basement
membrane by wavy dense osmiophilic, sausage-shaped deposits in MPGN type II (DDD).
This is the only time that EM can distinguish that the MPGN is complement mediated,
otherwise immunofluorescence findings are used to distinguish between complement-
mediated MPGN and immune-complex-mediated MPGN. Figure 2 contains images of LM,
IFM and EM features of MPGN.
The injury phase of immune complex mediated MPGN (figure 1) occurs due to the
deposition of immune complexes into the glomeruli, which activates the classical pathway
of the complement system, resulting in the formation of the membrane attack complex on
the mesangium and capillary walls. (1) The proliferative and reparative phases then
follow. Thus kidney biopsy specimens show immunoglobulin and complement deposition
on IFM.
The immune complex deposition in the glomeruli are due to a.) Antigen antibody
complexes from chronic infections mainly hepatitis C; b.) Increased immune complexes
secondary to autoimmune disease and c.) Glomerular deposition of monoclonal
immunoglobulins secondary to monoclonal gammopathies.(1)
8
Figure 2: MPGN findings on light, immunofluorescence and electron microscopy.
A-E Shows Immune-mediated MPGN
A: Light microscopy shows an MPGN pattern of injury
B: Immunofluorescence microscopy shows positive staining for IgM
C: Immunofluorescence microscopy shows positive staining for kappa light chains.
D: Immunofluorescence microscopy shows negative staining for lambda light chains.
E: Double-contour formation and subendothelial deposits (arrow) seen on EM.
F- J shows Complement-mediated MPGN
F: MPGN pattern of injury on LM
G: Bright C3 staining on immunofluorescence microscopy with negative staining for Immunoglobulin, C1q, kappa, and lambda light chains.
H: Electron microscopy shows dense osmiophilic deposits (arrow) along the glomerular basement membranes in dense-deposit disease.
I and J: mesangial (white arrows), subendothelial (black arrows), intramembranous (black arrowhead), and subepithelial deposits (white arrowheads)
and double contours in C3 glomerulonephritis on EM.
Reproduced with permission from Sethi S, Fervenza FC. N Engl J Med 2012;366:1119-1131, Copyright Massachusetts Medical Society.
9
Immune-complex-mediated MPGN associated with a monoclonal gammopathy has a
“monotypic immunoglobulin, usually kappa or lambda light chains restriction,” (1) while
MPGN associated with hepatitis C infection demonstrates IgM, IgG, C3 and kappa and
lambda light chains. (1) Autoimmune diseases associated with immune-complex-mediated
MPGN often have many immunoglobulins and complement proteins IgG, IgM, IgA, C1q,
C3 and kappa and lambda light chains.
The injury phase of complement- mediated MPGN (figure 3) occurs due to dysregulation
of the alternative complement pathway caused by autoantibodies to complement regulating
proteins or mutations in those proteins. (1,3,8) In the circulation, the alternative
complement cascade pathway is constantly active at low levels, thus activation is
tightly protected to prevent self-harm. Different complement regulating and
complement-inhibiting proteins work at different sites along the complement cascade
pathway. These proteins include factors H and I, factor H related proteins 1-5,
membrane cofactor protein (CD46), decay-accelerating factor (CD55), CD59,
complement receptor 1 and complement receptor of the immunoglobulin
superfamily. (1)
Mutations in anyone of the above can result in the dysregulation of the alternative
pathway. Hence immunoglobulins are not directly involved and on
immunofluorescence there is absence of immunoglobulins but shows marked
complement deposition. Patients typically have hypocomplementaemia, due to the
hyperactivity of the alternative complement cascade although some are recorded
with normal levels.(3)
10
Figure 3. Complement-Mediated MPGN.
Above is a schematic diagram of MPGN associated with dysregulation of the alternative pathway.
Mutations and antibodies to complement-regulating proteins result in the deposition of
complement factors of the alternative pathway and terminal complement complex causing the
Injury phase. The proliferative and reparative phases are as described for immune-complex–
mediated MPGN in Figure 1.
Antibodies (Y-shaped pink structures) are shown against complement factor H (CFH), factor I
(CFI), factor B, and C3 convertase (C3 nephritic factor).
Reproduced with permission from Sethi S, Fervenza FC. N Engl J Med 2012;366:1119-1131,
Copyright Massachusetts Medical Society.
11
From this new definition, familial MPGN Type II or DDD is now classified under
complement mediated MPGN due to abnormalities caused in the function and regulation of
the alternative complement pathway. (1) Complement mediated MPGN is then classified
into C3 glomerulonephritis and DDD but due to the transition noted between C3
glomerulonephritis and DDD on electron microscopy, they probably represent a
morphologic spectrum due to the underlying alternative complement pathway
dysregulation. (9) The diagnosis should be focused on the assessment of the alternative
pathway and mutations or antibodies to the complement binding proteins. (9)
MPGN type I and type III are now classified as immune complex mediated as they include
both immunoglobulin deposition and complement deposition. (9) It is then further divided
into the MPGN associated with chronic infections, autoimmune disease and monoclonal
gammopathy. Hepatitis C and infrequently hepatitis B are the chronic viral infections
attributed to the antigen antibody complexes deposited in immune complex mediated
MPGN, while chronic bacterial infections such as endocarditis, infected ventriculo-atrial
shunts, visceral abscesses, leprosy and meningococcal meningitis are also attributed. (9)
Other suggested infections that cause immune complex mediated MPGN are malaria,
schistosomiasis, mycoplasma and leishmaniasis. (9) The commonest autoimmune diseases
that result in increased immune complexes are systemic lupus erythematosus, Sjogren’s
syndrome and rheumatoid arthritis. (9) Lastly, immune complex mediated MPGN is
secondary to monoclonal gammopathies including the monoclonal gammopathy associated
MPGN. (9) There is a small allowance made that if none of the aforementioned conditions
exist, then it is labeled idiopathic MPGN. (9)
12
This classification thus excludes what was previously described as familial MPGN type I
and type III. To further complicate matters, C3 glomerulonephritis with subepithelial
deposits may be labeled MPGN type I, while C3 glomerulonephritis with intramembranous
and subepithelial deposits may be labeled MPGN type III, (9) yet with the new
classification they are identified as complement mediated MPGN, distinct from Type I and
III now classified as immune mediated MPGN. (9)
Epidemiologically, MPGN is a rare cause of glomerulonephritis and accounts for 7% of
adults (10) and 4-7% of children (2) with a primary renal cause of nephrotic syndrome and
accounts for 7-10% of biopsy proven glomerulonephritis. (1) The familial incidence has
been described as 2.6- 4% in primary MPGN type I and type III. (5) A familial form of
MPGN type III has been identified with an autosomal dominant pattern of inheritance that
is genetically linked to band 1q31-32. (4) The mode of inheritance has not been
adequately established, with current suggestions being autosomal dominant, x-linked
pattern of inheritance and autosomal recessive. (6,7) Although familial forms of MPGN
type I, type II and type III disease have been reported previously, none of these reported
families have been South African.
From 1976-2014 familial MPGN type I and III was reported in 30 patients. This diagnosis
was established after excluding other causes of MPGN and the type of MPGN was
confirmed on light microscopy (LM) and the type was based electron microscopy (EM)
findings. In the first study Berry et al. (11) presented two unrelated sibships. All four
patients presented within the first decade of life with proteinuria and hypertension.
13
In the first family “The M siblings” the brother (JM) was found to have MPGN type III on
LM and EM and on immunoflourscence there was moderate deposition of C3 and a small
amount of IgG. His sister (PM) had MPGN type I on LM and EM and on
immunoflourscence there was marked deposition of C3 and a small amount of IgG. The
serum C3 levels were low for both siblings at diagnosis, however PM’s serum C3 had
normalised at the time of publication. Both siblings were treated and maintained on
alternate day prednisone. They had improved clinically by the time of the article’s
publication.(11)
Figure 4: Pedigree M family Berry et al.
Figure 5: Pedigree G family Berry et al.
JM PM
Unaffected
Affected
Gender unknown
WG KG
The second sibship were labeled as “The G siblings”. They were two brothers who were
discovered incidentally when WG was found to be anaemic, hypertensive and proteinuric
14
on a routine preschool physical examination. His bother KG had previously been anaemic,
was then worked up for renal disease and was found to have severe renal dysfunction.
Neither brother had haematuria. Both were found to have MPGN type I on LM and EM,
and on IFM they were both found to have marked IgM and IgG deposition.
KG had marked C3 deposition while WG had minimal C3 deposition. However the biopsy
available from KG was the biopsy done 4 years after presentation and not the initial
biopsy. Throughout their diagnosis and followup, both brothers’ serum C3 levels remained
normal. Both brothers were placed on therapy with alternate day prednisone. However
their hypertension worsened on therapy and they both had a slow decline in renal
function.(11)
The conclusions drawn by Berry et al. (11) was that there was likely an underlying genetic
basis for the disease but that exposure to certain enviromental factors would result in
disease expression. Due to the different types of MPGN in the sibship of the M family,
they postulated that MPGN is multigenic in origin, modified by other genes which regulate
the immune responses resulting in the different types of disease expression. (11)
Interestingly in the G family, KG and his faher had C2 deficiency. However KG has an
affected brother who was not C2 deficient and his father, who was C2 deficient, had no
disease. This indicated that in this family the C2 deficiency was not associated with a
predisposition to MPGN (11) as previously shown by Kim et al.(12)
Stutchfield et al. (13) reported two related male patients with type 1 MPGN and they
surmised that the inheritance was an x-linked recessive disorder. Both patients were
proteinuric and presented within the first two years of life. The first patient (LA) presented
15
with persistent proteinuria originally detected on routine urine testing. He was found to be
normotensive and had no haematuria. He had normal renal function as well as normal
serum C3 levels. He later developed hypertension and had slowly deteriorating renal
function. His serum C3 level however remained consistently normal. On renal biopsy the
LM and EM findings were consistent with MPGN type 1. On immunofluorescence he had
depositis of IgG, IgM and minimal C3.(13)
NHLA
RT
IT
JH
CAJC
Unaffected
Demised
MPGN Presumed
Affected
Figure 6: Pedigree of family Stutchfield et al.
The second patient (NH), the maternal uncle of the first patient (LA), presented with
bipedal oedema and persistant proteinuria. He was normotensive, had microscopic
haematuria and normal renal function. He was also found to have normal serum C3 levels.
The renal biopsy features were that of MPGN type 1 on LM and EM. Immunofluorescence
however was not done. He received cyclophosphamide but the proteinuria persisted and his
renal function gradually deteriorated. He later became hypertensive. Throughout his course
16
his serum C3 and C4 levels remained normal. He demised from hypertensive
encephalopathy.(13)
In terms of the family’s pedigree, the grandmother (JH) of LA, the mother of NH, had only
one son (NH) who had biopsy proven MPGN. However her two other sons from different
fathers demised at a young age following nephritic illnesses. Her daughter (CA), a half
sister to NH, and the mother to LA, was healthy. Four of the grandmother’s (JH) ten
brothers died at a young age, with two having symptoms suggestive of nephritic/nephrotic
illness. Furthermore, one of the grandmother’s (JH) sisters had a son who also died in the
first decade of life from a similar illness. This was the first study with patients diagnosed
with MPGN under the age of two, reflecting an underlying genetic basis for the disease.
Together with the family pedigree an assesment was made of the mode of inheritance
being x-linked recessive.(13)
Sherwood et al. (14) described a father and son with MPGN, that the authors describe as an
autosomal dominant pattern of inheritance. The son at the age of four, was found to have
proteinuria on admission for a tonsillectomy. He was normotensive, had haematuria and
normal serum C3 and C4 levels. Renal ultrasound was normal and he also had normal
renal function at diagnosis. A renal biopsy was done when the son was 5 years old. While
on LM and EM the features were consistent with MPGN type I, immunofluorescence was
however negative for IgG, IgA, IgM and C3. His condition remained stable and he was not
receiving any treatment.(14)
17
Son
FatherAffected
Unaffected
Figure 7: Pedigree of family Sherwood et al.
His father at the age of twenty two years was found to be proteinuric and hypertensive. He
had a renal biopsy eight years later when he had end stage renal failure, which on LM and
EM had features of end stage renal disease due to MPGN. The type of MPGN was not
mentioned. Three years later at the age of thirty three, the father underwent renal
transplantation. No information is supplied regarding serum C3 and C4 levels, nor
regarding his treatment. Both father and son were found to have unusual facies as well as
unusual telangiectasia not associated with any known syndrome. The final conclusion from
the authors was that the mode of inheritance for this family was autosomal dominant. They
distinguished their family from the previous study by Stutchfiel et al. due to the unusual
skin condition seen in father and son.(14)
Bakkalogu et al. (7) described six patients from two families with MPGN. Family one (G
family) had first-degree consanguinity in the parents. All four sons were affected.The two
daughters and parents were unaffected. All four of the affected sons presented within the
first decade of life with proteinuria. Two (SG and AG) had hypertension at diagnosis and
one son (BG) developed hypertension during the course of the disease. The youngest son
18
(IG) presented at the age of 10 months. Two of the brothers (SG and BG) presented at the
age of three years and the other brother (AG) was seven years old at diagnosis. All had
normal renal function at diagnosis, however the patient AG had progressive worsening
renal function at the time of publication. All four brothers had normal serum C3 and C4.
Only three of the brothers’ biopsy results were available as the eldest brother (AG) had had
the diagnosis of MPGN made previously. Of the three biopsies, all were in keeping with
MPGN type I. In the patient SG, no immunoflourescence was done. In the other two
brothers (BG and IG), there was mainly C3 deposition. One of the father’s (DG) brothers
died of an illness suggestive of nephritic syndrome; no further information was available
about this family member. (7)
IGHGAGSGBGKG
TG DG MG CG ZG NG
Unaffected
Demised
MPGN Presumed
Affected
Figure 8: Pedigree of the G family Bakkalogu et al.
19
The second family “The Y family” had unrelated parents and four sons and one daughter.
Two brothers presented with hypertension, proteinuria and haematuria at the age of nine
(MY) and thirteen (FY). Their initial serum C3 and C4 levels were low but subsequently
normalised. On biopsy, the LM and EM finding were consistent with MPGN type I and on
immunoflourescence, MY had only C3 deposition while FY had C3 and IgA deposition.
No abnormalities were detected in the serum complement profile in both families. On
review of both families, the mode of inheritence is proposed to be autosomal dominant or
an X-linked inheritance with incomplete penetrance, as members in more than one
generation were affected. However there was a different progression of disease between
MY and FY which the authors postulated as indicating a multigenic orgin for MPGN, with
a gene predisposing to MPGN but requiring modification by other genes affecting immune
control, resulting in the different modes of disease expression (7) , a similar finding to that
of Berry et al.(11)
Abderrahim et al. (15) reported two brothers who were both diagnosed with MPGN I.
There was first degree consanguinity in the parents. The first patient HL presented at the
age of 17 with hypertension, bilateral pitting oedema, proteinuria and macroscopic
haematuria. He had a normal renal ultrasound and normal serum C3 and C4 and mild renal
dysfunction. His renal biopsy on LM and EM was consistent with MPGN type I. There
was no comment made regarding immunoflourescence. HL was started on antiplatelet
agents and beta blockers. Eighteen months later his renal function had normalised and he
had trace proteinuria. His complement levels were normal.(15)
20
Unaffected
MPGN Biopsy proven
HLHA
Figure 9: Pedigree of family Abderrahim et al.
HL’s elder brother HA presented with hypertension, haematuria and proteinuria at the age
of eighteen. His renal biopsy findinging on LM and EM were in keeping with MPGN type
I. He had renal failure at diagnosis and demised three years later from end stage renal
disease. Limited data is available regarding HA as he was diagnosed and treated at a
different hospital than that of the authors. Regarding the presentation and progress of the
two brothers, the authors postulated that familial MPGN is a multifactorial disease. (15)
Bogdanovic et al. (5) reported two siblings with MPGN. Patient 1 was a boy who was 5
years old when he presented with bipedal oedema, hypertension, haematuria and
proteinuria. He had low serum C3 and C4 levels. LM and EM findings were of MPGN
type I. Immunoflourescence showed IgG, IgM, IgA and C3 deposits. Initally he was started
on alternate day prednisone, followed by cyclosporine and then cyclophosphamide. His
nephrotic syndrome resolved when he was nine, but he remained with residual proteinuria.
21
Patient 1 Patient 2
Unaffected
Affected Biopsy proven
Chronic Pyelonephritis
Figure 10: Pedigree of family Bogdanovic et al.
Patient 2 was a girl who presented only with proteinuria when she was at the age of 3
years. Her disease progressed and when she was six years old, she presented with
nephrotic syndrome. Her serum C3 and C4 levels were persistently normal. On LM and
EM, she had findings in keeping with MPGN type III. She had C3, IgG, IgM and IgA
deposits on immunoflourescence. She received the same treatment as her brother, but she
remained nephrotic and her renal function declined at the age of seven and a half years.
In terms of the family history, the parents were unrelated and the father was healthy. The
mother developed hypertension and advanced renal failure at the age of eighteen during
her first pregnancy, which was terminated by miscarriage. Her renal function declined and
three years later regular haemodialysis was started. Her renal failure after workup was
attributed to chronic pyelonephritis. She was transplanted at the age of tewnty-two and her
graft renal function was excellent. She went on to deliver her two children post
transplantation. Autosomal dominant disease possibly associated with MPGN was
excluded in this family. (5)
22
The authors reviewed the other families previously published with MPGN and found no
reported abnormalities of complement which corresponded with their patients. They also
found that different HLA haplotypes were associated with MPGN in the different studies.
The highest frequency was that of HLA-A2. However, previously it was noted that patients
with haplotype HLA-B8 had a poorer prognosis for kidney function. However, their
patients had HLA-A24, B27, Bw4, DR11, DR52 and DQ3 in common, and while having
similar clinical pictures, they had different types of MPGN and despite the same treatment,
they had markedly different outcomes. Thus, their finding was that the mode of inheritance
is probably multigenic in orgin, with an underlying gene predisposing to MPGN but
modified by other genes. (5)
Motoyama et al. (6) published a case report of MPGN type I diagnosed in a mother and
her daughter. Case 1, the daughter at the age of fourteen, had microscopic haematuria and
proteinuria detected on routine school urinary testing. She was normotensive and had low
serum C3 levels, but normal C4 levels. LM findings on biopsy were that of MPGN type I.
No glomeruli were included in the specimen for EM. On immunoflourescence there were
only C3 deposits. She was treated with methylprednisone for three days followed by
prednisone. The proteinuria disappeared and the prednisone was stopped in a month. She
continued to have microscopic haematuria and hypocomplementaemia. (6)
23
Case 2
Case 1
Unaffected
MPGN Biopsy proven
Figure 11: Pedigree of family Motoyama et al.
Case 2, the mother, developed oedema, hypertension, proteinuria, and microscopic
haematuria when she was nine years old. Both serum C3 and C4 levels were low. The
oedema and hypertension improved a month later but the haematuria, proteinuria and
hypocomplementaemia persisted. The renal biopsy findings on LM and EM were in
keeping with MPGN type I and on immunoflourescence, only C3 deposits were found.
She was started on steroid therapy but continued to have proteinuria. She defaulted therapy
at the age of fifteen and presented again at the age of twenty four, when she was found to
be normotensive, with no oedema but persistent proteinuria. She had low serum C3 and
normal serum C4 but mild renal dysfunction.
24
She was started on dipyridamole and had three successful pregnancies, but developed
nephrotic syndrome in the first and third pregnancies. During the last pregnancy her renal
function declined and she received methylprednisone and her renal function improved. At
the time of publication she had normal renal function with low serum C3 and mild
proteinuria. Only one of her daughters had MPGN type I, the other children were healthy.
The authors postulated that the mode of inheritance is unclear, and while there may be an
underlying genetic basis, it is likely that enviromental factors are a cause, due to the
discrepencies in clinical and pathological findings in family members. (6)
The last two familial studies are both from Ireland. The first family described by Neary et
al. the index case (subject 105), a 51 year old male, presented with hypertension,
haematuria, proteinuria and renal dysfunction. Twelve years earlier he had been healthy
with no haematuria or proteinuria on donation of a kidney to his son (subject 213). While
his complement profile was normal, his renal biopsy on LM had features consistent with
MPGN and EM features suggested it to be of type III. On IFM there was only C3
deposition. He was treated with steroids and pulsed with cyclophosphamide and still has
persistent renal dysfunction.
His son had presented at the age of four years with nephrotic syndrome unresponsive to
steriods. He also had a low serum C3 and normal C4 and was found to have microscopic
heamaturia. His renal biopsy on IFM showed C3 deposition and on EM the MPGN was
listed as type III MPGN with subendothelial, intramembranous and subepithelial basement
membrane depositis. Six years later, at the age of ten years he received a kidney transplant
from his father for ESRD. On a renal biopsy specimen of the transplanted kidney, two
years after transplant, the speciment showed MPGN type III with C3 deposition on IFM.
25
Six years post transplant he developed graft failure and receieved a second graft. It is not
stated whether it was cadaveric or familial tranplant. Up to publication he was doing well
but remained proteinuric.
His brother (subject 212) and sister (subject 214) were investigated for nephrotic
syndrome. Both of their renal biopsy specimens were in keeping with MPGN type I. Both
had normal serum complement levels and normal renal function. Their paternal aunt
(subject 103) also developed ESRD at 51 years of age and her biopsy, done at the age of
twenty-six years, was also consistent with MPGN. She was found to have normal serum
complement and received a renal transplant at the age of fifty-four years.
The index patient’s sister (subject 107) and niece (subject 223) , on screening were found
to have haematuria and proteinuria and on renal biopsy MPGN type III. They both also had
normal serum complement levels.
Neary et al. in a follow up study of this study found a linkage of chromosome 1q to MPGN
type III with an autosomal dominant pattern of inheritance. (4) This locus was found to
contain genes that code regulators of the complement pathway. The authors concluded that
MPGN type III was more likely to be steroid resistant and typically progressed to ESRD
within ten years after presentation. (4)
26
001
107101 102
104
105
114
108
115
110
209 210208 211
201 202 205203 204
214213 215
109 116
112
223220 221 222
224 225 226
227 228
103113
206 207
111106
216 218217 219
212
Unaffected
Demised
MPGN Presumed
Affected
Figure 12: Pedigree of family Neary et al.
27
Redahan et al. described 3 separate families all with familial MPGN, however the third
family was diagnosed with MPGN of dense deposit disease type (type II MPGN) and thus
is excluded from this study. The first family had two affected members.
The index case was 16years of age when she presented in renal failure. She had no other
medical history and on renal biopsy was found to have MPGN with immune complex
deposition. Within five years she had progressed to ESRD and was initiated on RRT. She
received a cadaveric transplant a year later at the age of 22 years which failed due to
chronic allograft nephropathy, which also caused the failure of her second cadaveric
transplant. Her third graft remained well functioning at time of the publication. No
evidence of recurrence was found in any of the grafts.
Her brother was diagnosed with renal disease at the age of eighteen and his biopsy showed
MPGN with immune complex deposition. He received a cadaveric transplant at the age of
twenty two years after starting RRT at the age of twenty-one years.(16)
28
Unaffected
Affected
MPGN Presumed
Demised
1A 1B
Figure 12: Pedigree of family 1 Redahan et al.
2A 2B
Figure 13: Pedigree of family 2 Redahan et al.
Unconfirmed kidney disease
2C
29
The second family’s index case was a twenty-two year old male (case2A) who presented
with a severe headache, hypertension and renal dysfunction. He was found to have
haematuria, proteinuria and low serum complement levels. On renal biopsy he was found
to have a moderate amount of immunoglobulin and complement deposition. Within twelve
months he had progressed to ESRD and started RRT. A year later he received a kidney
transplant from a living related donor, one of his siblings.(16)
A routine examination of the youngest brother (case 2B) revealed proteinuria and a renal
biopsy was done, which demonstrated MPGN with immunoglobulin and complement
deposition. At seventeen years of age he received a kidney transplant from one of his
siblings, although it was done preemptively. Six years later he received a second
transplant, from another sibling, after graft failure occurred due to disease recurrence. The
second eldest brother (case 2C) developed microscopic haematuria at the age of thirty-one
years and underwent a renal biopsy with had features of an IgA nephropathy. He however
remained well and didn’t progress in terms of his renal disease. Redahan et al then
discusses the possible inheritance pattern of family 1 as autosomal recessive and family 2
as x-linked or autosomal recessive.(16)
From the above, it can be seen that very few families world wide have been described with
familial MPGN and none have been South African. Futhermore, since the new
classification of MPGN has come into place, there is increasing confusion as to which
category familial MPGN falls into. By examining this South African family and doing a
systematic review of the literature, a larger case series is obtained which allows for an
improved understanding of the conundrum that is familial MPGN type I and Type III.
30
AIMS
1. The aim of this study is to determine the incidence of MPGN within the family of
our index patient as well as to assess if there is a Mendelian inheritance pattern
within this family.
2. Further more a systematic review was undertaken to review the available literature
on familial MPGN and to classify familial MPGN within the new definitions of
MPGN.
31
OBJECTIVES
1. Determine the incidence of MPGN within the family of our index patient.
2. Assess the Mendelian inheritance pattern within this family
3. Review and compare with previous published studies.
4. Classify familial MPGN
32
METHODS
Ethical Approval
Ethics approval was obtained from the Human Research Ethics Committee (Medical) of
the University of the Witwatersrand, certificate number M120446, for a prospective study
of the available family members of the index patient and a retrospective study of those
family members already worked up or diagnosed and been treated for MPGN type1.
Study Population
All contactable family members of the index patient that consented to participate in the
study were included. The four family members, including the one deceased family
member, that attended the Renal Unit at the Charlotte Maxeke Johannesburg Academic
Hospital (CMJAH) were also included as part of the retrospective study.
Data Collection
The study was an open study with the primary investigator knowing the results for all
participants included in the study. With regards to the data collection, each participant was
given a coded number and all data collected was kept under this code to maintain
confidentiality, with only the primary investigator knowing the coding system.
The data collected from the Renal Unit at CMJAH for those family members already
worked up for the disease, included the patient’s history, clinical presentation, blood
33
results as well as their renal biopsy results. All other asymptomatic contactable family
members that consented to participate in the study were included and participants provided
a urine sample, which was tested for proteinuria and haematuria with Uricheck M10 Urine
Reagent Strips Omnipharma (Pty) Ltd.
Histories were obtained from the asymptomatic family members to determine if other
diseases and comorbidities were present that would affect the results. If a co-morbidity was
found, they were excluded from the study. A blood sample in an EDTA tube was also
taken and kept at minus 20 degrees Celsius for DNA extraction for a follow up study to
assess if there is an underlying genetic mutation within this family. If family members
were found to have proteinuria and/or haematuria with no other cause for the proteinuria
and/or haematuria, they were considered positive for this study and referred for further
work up including a renal biopsy at CMJAH Renal Unit. The data obtained from family
members diagnosed with MPGN was collated with the information available from previous
reports.
Systematic review
For the Systematic review, the two following terms were searched in PubMed separately,
familial MPGN and inherited MPGN. The term mesangiocapilliary is used interchangeably
for MPGN on PubMed, and using the term mesangiocapilliary glomerulonephritis in place
of MPGN has the same results as for the MPGN search. Combining the two searches,
ninety-seven articles were found but only ten were applicable. The eighty-seven articles
that were excluded pertained studies regarding animal MPGN studies, Type II MPGN
(DDD) or C3 nephropathy, and studies that were MPGN associated with other illnesses
34
including those associated with haemolytic uraemic syndrome and familial Mediterranean
fever. The reports that did not include actual familial studies in the research report were
also excluded. Of those ten articles that were applicable, two were concerning the same
family (4,17) , one study was a descriptive study (17) and the other looked at the genetics
pertaining to the family studied. (4) Reports of MPGN in siblings prior to 1980 had very
limited data especially regarding the biopsy results and immunofluorescence and as such
they were unable to be reclassified according to the new definitions of MPGN and thus
were also excluded.
A Spanish study by Robles et al. (18) appeared to be applicable, however all attempts to
obtain the study including writing to the authors has been unsuccessful. The studies that
were applicable and able to be obtained were assessed and their data combined and where
possible reclassified according to the immunofluorescence results. In the report by
Redahan et al. (16) Family 3 was excluded from the systematic review as the family
members were diagnosed with MPGN type II which was an exclusion criteria for the
systematic review.
35
RESULTS
36
The Study Family
17 of the 20 contactable family members were available and consented to participate in the
study. Four members (22%) were affected. The three who were proteinuric and without
any comorbidities were the three members currently attending the renal unit at CMJAH.
The demographics and clinical presentation of the affected family members can be found
in table 1. Their family tree can be found in figure 10.
Our index patient (413) presented to the renal unit at CMJAH at the age of seventeen with
nephrotic syndrome. At the age of thirteen years, she had presented at another institution
with bipedal oedema, hypertension and proteinuria and was diagnosed with nephrotic
syndrome secondary to idiopathic MPGN type I and had been on oral steroids (prednisone
5mg alternate days) since then. Despite the corticosteroid use, she remained proteinuric
Table 1: Demographics and clinical data
Patient Designation 304 405 404 413*
Gender Male Male Male Female
Age at diagnosis
(years) 29 15 18 13
Follow up (years) 1 8 5 8
Hypertension Yes No No Yes
Hypertensive at follow
up Yes Yes No Yes
Haematuria Yes Yes Yes Yes
Persistant Haematuria Yes Yes Yes Yes
Proteinuria Yes Yes Yes Yes
Urine protein g/24hr 4.9 14.0 10.4 3+ **
Persistant Proteinuria Yes Yes Yes Yes
ESRD age
Demised
before follow
up
19 No No
Table with the patient demographics, clinical presentation, residual clinical
characteristics and age at diagnosis of end stage renal disease (ESRD) IP: Index Patient
* Index patient; **only data from qualitative urinanalysis available as patient previously
diagnosed at another institution.
37
and was admitted by the renal unit at CMJAH for a repeat renal biopsy. The rest of her
medication included perindopril 8mg daily, telmisartan 40mg daily and atorvastatin 20mg
daily. She had normal renal function at both renal biopsies and her serum C3 and C4 levels
have always remained normal. She had no co-morbidities her initial lab results can be
found in table 2.
Table 2: Laboratory data
Patient Designation 304 405 404 413*
Serum Creatinine umol/l 238 97 71 14
Serum Albumin g/l 16 34 39 26
Serum C3 Normal Normal Normal Normal
Serum C4 Normal Normal Normal Normal
GFR at diagnosis mL/min 32 71 128 182
Creatinine at follow up
umol/L 265 906 93 170
GFR at follow up mL/min 29 8 96 40
Table with the laboratory data pertaining to the affected family members
* Index patient;
The light microscopy and immunofluorescence features of her renal biopsy were in
keeping with an immune-complex mediated glomerulonephritis with a
membranoproliferative reaction pattern favoured to represent those of MPGN type I. As
shown in table 3, she had IgG and C3 deposition on IF thereby reclassifying her as an
immune-complex mediated MPGN. All other causes of proteinuria were excluded as well
as other causes of immune-complex mediated MPGN. Despite immunosuppressive
treatment (tacrolimus and glucocorticoids at higher doses) her renal function continued to
steadily decline to a glomerular filtration rate (GFR) of 40mL/min (originally 182mL/min)
and she remained proteinuric. She did not develop any complications post biopsy nor from
her treatment.
38
Table 3: Renal Biopsy Features and MPGN Classification
Patient
Designation
Classification at
diagnosis
Immunofluorescence Microscopy New
Classification IgG IgM C3
304 MPGN Not done Not done Not done IM features on
light microscopy
405 MPGN TYPE I Yes Yes Yes IM
404 ATN No No No ATN
413* MPGN TYPE 1 Yes No Yes IM
Table with the renal biopsy features and the original diagnosis made with the old
classification and the new classification based on the biopsy results. * Index patient;
ATN: Acute tubular necrosis; IM: Immune complex mediated
Two of her first cousins (404 and 405) who are brothers, and her one maternal uncle (304)
had also attended the renal unit at CMJAH. Her two cousins were from a consanguineous
marriage, with their parents being first cousins. 405 presented prior to his brother (404) to
the CMJAH paediatric unit, at the age of 4 years, with jaundice and splenomegaly
following an acute hepatitis A infection. On a follow up visit at 11 years of age, he was
found to have asymptomatic microscopic haematuria and he was referred to CMJAH
paediatric renal unit.
He remained asymptomatic and all workup was normal, a renal biopsy was not done. He
then moved to Cape Town. At the age of 15 years, he returned to the paediatric unit at
CMJAH with anasarca and hypertension and was found to have marked proteinuria and
haematuria and was worked up for nephrotic syndrome. He had normal serum C3 and C4
levels and a normal GFR. All other work up for his nephrotic syndrome was negative. He
also tested negative for all causes of immune-complex mediated MPGN. He had a normal
renal and abdominal ultrasound and the portal hypertension and splenomegaly, previously
diagnosed at four years of age, had all resolved and were normal.
39
His renal biopsy’s histological features were in keeping with an immune-complex
mediated glomerulonephritis with a membranoproliferative pattern and a mild to moderate
acute tubular necrosis. The electron microscopy findings were supportive of an immune
complex mediated MPGN type 1. IFM showed marked IgG deposition, IgM and C3
staining thereby his new classification was thus immune-complex mediated MPGN.
He was started on daily oral prednisone at 1mg/kg and had three cycles of
cyclophosphamide, which resulted in resolution of the haematuria and a decrease in the
proteinuria although he still remained proteinuric. The oral prednisone was then weaned
and stopped after 11 months of treatment. Seven months later he was then restarted on oral
prednisone and Mycophenolate Mofetil (trade name: Cell Cept) 500 mg daily as his
proteinuria had increased and he was transferred to the adult renal unit at CMJAH. Despite
immunosuppressive treatment he remained proteinuric and had a progressive decline in
renal function ultimately resulting in end stage renal disease (ESRD) four years after
diagnosis. He is currently on renal replacement therapy and awaiting renal transplantation.
404, brother to 405, presented at the age of nineteen years with nephrotic syndrome. His
renal function was normal at the time and his serum C3 was slightly raised and he had a
normal serum C4. His work up for all causes of nephrotic syndrome was negative and he
had a normal renal and abdominal ultrasound. On renal biopsy LM and EM features were
in keeping of an acute tubular necrosis (ATN). On immunofluorescence there was no
complement and immunoglobulin deposition staining. Despite extensive workup, no cause
of the ATN was found and a final assessment of mild acute tubular necrosis of unknown
cause was made. He however continued to have proteinuria and was started on daily
prednisone at 1mg/kg. The proteinuria gradually decreased and after the fourteen month,
40
the prednisone was stopped. His blood pressure also normalized on treatment. After the
prednisone was stopped he has followed up at the renal unit irregularly due to work
commitments.
In 2013 he returned to the unit and was found have mild proteinuria and his GFR has
steadily declined. At a previous visit, his GFR had been lower than his original GFR but no
follow up occurred due to the patient being lost to follow up. His GFR has been steadily
declining, although not at the same rate as his younger brother, and his most current GFR
is 93ml/min (original GFR at presentation was 128ml/min). Due to his work commitments,
he was unable to attend the renal unit regularly and there has been a delay in obtaining a
repeat renal biopsy. In light of the fact that he presented with nephrotic syndrome and the
biopsy results, despite being reviewed, were out of keeping with his nephrotic syndrome
and as currently he remains proteinuric , he is undergoing active work up again for a repeat
renal biopsy.
Six years earlier 304, the maternal uncle of our index patient, was referred to CMJAH
at the age of twenty nine years after presenting to a private health care facility where
he was diagnosed with nephrotic syndrome with renal failure. He was unemployed
and had no funds for medical care and hence he had not sought medical care sooner.
He was hypertensive and had anasarca. There were no other abnormalities noted on
examination. He had normal serum C3 and C4 and on history had no co-morbidities.
On renal biopsy, only a single core of tissue was submitted and sent for light
microscopy. Histopathology did not receive any tissue specimens for
immunofluorescence microscopy and electron microscopy. LM findings of the renal
biopsy were in keeping with an immune-complex mediated diffuse proliferative
41
glomerulonephritis with a membranoproliferative reaction pattern, typical for the
diagnosis of MPGN. As specimens for IFM were however not submitted it was difficult
to distinguish between MPGN type I and type III.
He was started on cyclophosphamide and oral prednisone and his GFR increased to
63mL/min (previously it was 32mL/min. He developed Escherichia coli sepsis after
the cyclophosphamide dose. He improved on antibiotics and was discharged home.
Two months later, on admission for the second cycle of cyclophosphamide, his GFR
had decreased again now to 31mL/min and he presented with anasarca, seizures and
pulmonary oedema. He was started on renal replacement therapy, which was stopped
just prior to discharge as his renal function had again improved after the
cyclophosphamide was given. A few months later he suddenly demised.
Unfortunately no documents could be traced regarding the events leading up to his
death. However, after discussion with his relatives, myocardial infarction seems the
most likely cause of his death.
Three other family members (102; 201; 202; 305) demised from renal disease in their
fourth decade of life. Although the formal diagnosis is unknown, based on the history
described by family members, MPGN is suspected.
The inheritance pattern does not appear to be a clear Mendelian pattern. The two brothers
were from a consanguineous marriage that would suggest autosomal recessive, however
more male family members are affected which would suggest x-linked recessive, but that
does not account for the female family members. Also in other consanguineous marriages,
42
no siblings were affected. This suggests while there is a definite underlying genetic basis,
it is either autosomal recessive with incomplete penetrance or multigenic.
43
101 102
201
202
203 204 205 206 207 208 209 210
301 302
303 308
310
311 312
304 305306 307
309
401 402
403 404 405
406 407408
409
Divorced
410
411
412 413 414 415
Probable affected on history
Consanguinous marriageAffected Biopsy proven
Likely affected, pending
biopsy
Unaffected
DemisedFigure 15: Pedigree of South African Family
100First number indicates
generation
44
Systematic review Results
The nine reports contained information regarding twelve families that combined with this
study’s family takes the number to thirteen families with thirty-four family members.
There is a definite male predominance with twenty-five being male and only nine being
female. The mean age was fifteen years, with a median of fourteen years and a mode of ten
years at diagnosis. The eldest family member was fifty-one years at diagnosis. The age
range was forty-eight years with a standard deviation of nine years. Table 4 contains the
demographics of the family members. The mean follow up was six years. The mean
creatinine at diagnosis was 134umol/L with a median of 66umol/L and a mode of
53umol/L. The mean age at which ESRD occurred was twenty-three years, with a median
and mode of twenty-one years. The clinical presentation was mainly that of nephrotic
syndrome with hypertension and proteinuria (table 5).
Table 7 contains the biopsy results and the previous MPGN classification as well as the
new classification. In those family members where immunofluorescence was not
performed, the same classification was given as the other members of their family. From
this, it is noted that two distinct groups form; one that is complement-mediated and the
other that is immune complex mediated, which the South African family falls into. The
two groups are split from this point on. The studies by Sherwood et al. and Abderrahim et
al. have too little information to be able to reclassify these families and thus they are not in
the subdivided groups of immune complex mediated and complement-mediated.
45
Table 4: Demographics
Author Reference Patient
Designation Gender
Age at
Diagnosis
(years)
Follow up
(years) Age at ESRD (years)
Berry et al. (11) JM Male 10 5 No
Berry et al. PM Female 9 2 No
Berry et al. WG Male 5 4 No
Berry et al. KG Male 7 5 No
Strutchfield et al.
(13) LA Male 1yr 9months 2 No
Strutchfield et al. NH Male 1yr 5 months 6 5 Demised
Sherwood et al. Father Male 22 8 30
Sherwood et al. Son Male 4 1 NR
Abderrahim et al. HI Male 17 2 No
Abderrahim et al. HA Male 18 3 21
Bakkaloglu et al. SG Male 3 1 NR
Bakkaloglu et al. AG Male 10 7 10
Bakkaloglu et al. BG Male 3 6 NR
Bakkaloglu et al. IG Male 10 1 NR
Bakkaloglu et al. MY Male 9 4 NR
Bakkaloglu et al. FY Male 13 2 NR
Bogdanovic et al. SC Male 5 5.5 No
Bogdanovic et al. MC Female 5 yr. 6 months 3 8.5
Motoyama et al. Case 1 Female 14 1 NR
Motoyama et al. Case 2 Female 9 31 NR
Redahan et al. 1A Female 16 22 21
Redahan et al. 1B Male 18 13 21
Redahan et al. 2A Male 22 2 23
Redahan et al. 2B Male 15 2 17
This Report 304 Male 29 1 29 Demised
This Report 405 Male 15 8 19
This Report 404 Male 18 5 No
This Report 413* Female 13 8 No
Neary et al. 213 Male 4 NR 10
Neary et al. 105 Male 51 NR No
Neary et al. 212 Male 28 NR No
Neary et al. 214 Female 21 NR No
Neary et al. 103 Female 25 NR 54
Neary et al. 223 Female 16 NR No
Mean 15 6 23
Median 14 4 21
Mode 10 2 21
Standard Deviation 9,85
6,77
12,51
Table containing the demographics of all affected family members:
ESRD: End Stage Renal Disease * Index patient
46
Table 5: Clinical presentation
Author Reference
Patient
Designation Hypertension Haematuria Proteinuria
Berry et al. JM Yes Yes Yes
Berry et al. PM Yes Yes Yes
Berry et al. WG Yes No Yes
Berry et al. KG Yes No Yes
Strutchfield et al. LA No No Yes
Strutchfield et al. NH No Yes Yes
Sherwood et al. Father Yes NR Yes
Sherwood et al. Son No Yes Yes
Abderrahim et al. HI Yes Yes Yes
Abderrahim et al. HA Yes Yes Yes
Bakkaloglu et al. SG Yes NR Yes
Bakkaloglu et al. AG Yes NR Yes
Bakkaloglu et al. BG No NR Yes
Bakkaloglu et al. IG No NR Yes
Bakkaloglu et al. MY Yes NR Yes
Bakkaloglu et al. FY Yes NR Yes
Bogdanovic et al. SC Yes Yes Yes
Bogdanovic et al. MC No Yes Yes
Motoyama et al. Case 1 No Yes Yes
Motoyama et al. Case 2 Yes Yes Yes
Redahan et al. 1A NR NR NR
Redahan et al. 1B NR NR NR
Redahan et al. 2A Yes Yes Yes
Redahan et al. 2B NR NR NR
This Report 304 Yes Yes Yes
This Report 405 No Yes Yes
This Report 404 No Yes Yes
This Report 413* Yes Yes Yes
Neary et al. 213 Yes No Yes
Neary et al. 105 Yes Yes Yes
Neary et al. 212 Yes Yes Yes
Neary et al. 214 No Yes Yes
Neary et al. 103 Yes NR Yes
Neary et al. 223 Yes Yes Yes
Table depicting the clinical presentation of all the family members
* Index patient
47
Table 6: Laboratory Data
Author Reference Patient
Designation
Serum Creatinine
umol/l Serum Albumin g/l Serum C3 Serum C4
GFR at
diagnosis
Berry et al. JM 27 18 Decreased NR NR
Berry et al. PM 248 15 Decreased NR NR
Berry et al. WG 44 28 Normal Normal NR
Berry et al. KG 159 30 Normal Normal NR
Strutchfield et al. LA 41 31 Normal NR 76
Strutchfield et al. NH 40 24 Normal NR 77
Sherwood et al. Father NR NR NR NR NR
Sherwood et al. Son 96 NR Normal Normal 140
Abderrahim et al. HI 142 20 Normal Normal NR
Abderrahim et al. HA 230 NR Normal Normal NR
Bakkaloglu et al. SG 53 22 Normal Normal Demised
Bakkaloglu et al. AG 265 25 Normal Normal NR
Bakkaloglu et al. BG 53 25 Normal Normal NR
Bakkaloglu et al. IG 53 24 Normal Normal NR
Bakkaloglu et al. MY 796 26 Decreased Decreased NR
Bakkaloglu et al. FY 177 24 Decreased Decreased NR
Bogdanovic et al. SC 35 13 Decreased Decreased 147
Bogdanovic et al. MC 62 23 Normal Normal 145
Motoyama et al. Case 1 62 45 Decreased Normal NR
Motoyama et al. Case 2 62 29 Decreased Decreased NR
Redahan et al. 1A NR NR NR NR NR
Redahan et al. 1B NR NR NR NR NR
Redahan et al. 2A NR NR Decreased Decreased NR
Redahan et al. 2B NR NR NR NR NR
This Report 304 238 16 Normal Normal 27
This Report 405 97 34 Normal Normal 71
This Report 404 71 14 Normal Normal 128
This Report 413* 39 26 Normal Normal 182
Neary et al. 213 NR 21 Decreased Normal NR
Neary et al. 105 133 33 Normal Normal NR
Neary et al. 212 NR 26 Normal Normal NR
Neary et al. 214 NR 28 Normal Normal NR
Neary et al. 103 NR 30 Normal Normal NR
Neary et al. 223 NR 40 Normal Normal NR
Mean 134 21
Median 66 21
Mode 53,04 Not Calculated
Standard Deviation 159,92 7,48
Table depicting the laboratory data of all the family members
NR: Not recorded; * Index patient
48
Table 7: Biopsy Results
Author Reference Patient
Designation
Previous
classification IFM IgG IFM IgM IFM C3
New
Classification
Berry et al. JM 3 Yes low Yes Yes CM
Berry et al. PM 1 Yes low Yes Yes CM
Berry et al. WG 1 Yes Yes Yes IM
Berry et al. KG 1 Yes Yes Yes IM
Strutchfield et al. LA 1 Yes Yes Yes IM
Strutchfield et al. NH 1 Not done Not done Not done IM
Sherwood et al. Father 1 Not done Not done Not done ?
Sherwood et al. Son 1 No No No ?
Abderrahim et al. HI 1 Not done Not done Not done ?
Abderrahim et al. HA 1 Not done Not done Not done ?
Bakkaloglu et al. SG 1 NR NR NR CM
Bakkaloglu et al. AG 1 NR NR NR CM
Bakkaloglu et al. BG 1 NR Yes Yes CM
Bakkaloglu et al. IG 1 NR Yes Yes CM
Bakkaloglu et al. MY 1 NR NR Yes CM
Bakkaloglu et al. FY 1 NR NR Yes CM
Bogdanovic et al. SC 1 Yes Yes Yes IM
Bogdanovic et al. MC 3 Yes Yes Yes IM
Motoyama et al. Case 1 1 No No Yes CM
Motoyama et al. Case 2 1 No No Yes CM
Redahan et al. 1A 1 Yes Yes No IM
Redahan et al. 1B NS Yes Yes No IM
Redahan et al. 2A 1 Yes Yes Yes IM
Redahan et al. 2B 1 Yes Yes Yes IM
This Report 304 1 Not done Not done Not done IM on LM
This Report 405 1 Yes Yes Yes IM
This Report 404 1 No No No ATN
This Report 413* 1 Yes No Yes IM
Neary et al. 213 3 No No Yes CM
Neary et al. 105 3 No No Yes CM
Neary et al. 212 3 No No Yes CM
Neary et al. 214 3 No No Yes CM
Neary et al. 103 3 NR NR NR CM
Neary et al. 223 3 No No Yes CM
Table containing the biopsy results of affected family members
IFM: Immunofluorescence microscopy; CM: Complement mediated; IM: Immune complex Mediated;
ATN: Acute tubular necrosis; ? Not enough information supplied for classification. * Index patient
49
Fourteen family members were included in the IM group from five reports. The mean and
median age of diagnosis, of the family members in the IM group was 15 years. The mean
follow up was six years. Most of the patients presented with proteinuria but quite a few
studies did not go into detail regarding the clinical presentation. One report (Redahan et
al.) did not include any information regarding the laboratory data. (16) The other patients,
however, had a mean serum creatinine of 83umol/L and a mean serum albumin of 24g/L.
The mean age of ESRD was twenty years. Due to the small numbers, very little data is
available to carry out a statistical analysis. The South African family is the largest family
of affected family members in the immune-complex mediated group.
Table 8: Immune complex mediated MPGN demographics
Author
Reference
Patient
Designation Gender
Age at
Diagnosis
(years)
Follow up
(years)
Previous
MPGN
New
Classification
Berry et al. WG Male 5 4 1 IM
Berry et al. KG Male 7 5 1 IM
Strutchfield et
al. LA Male 1 2 1 IM
Strutchfield et
al. NH Male 1 5 1 IM
Bogdanovic et
al. SC Male 5 5 1 IM
Bogdanovic et
al. MC Female 5 3 3 IM
Redahan et al. 1A Female 16 22 1 IM
Redahan et al. 1B Male 18 13 NS IM
Redahan et al. 2A Male 22 2 1 IM
Redahan et al. 2B Male 15 2 1 IM
This Report 304 Male 29 1 1 IM
This Report 405 Male 15 8 1 IM
This Report 404 Male 18 5 ATN ATN
This Report 413* Female 13 8 1 IM
Mean 15 6
Median 15 5
Mode 5 2
Standard
Deviation
7,29
5,78
Table containing the demographics for the family members with immune complex mediated MPGN
NS: Not specified; ATN: Acute Tubular Necrosis; IM: immune complex mediated; * Index patient
50
Table 9: Immune mediated clinical presentation and residual findings
Author
Reference
Patient
Designation Hypertension
Persistant
HTN Haematuria
Persistant
Haematuria Proteinuria
Persistant
Proteinuria
Berry et al. WG Yes Yes No No Yes NR
Berry et al. KG Yes Yes No No Yes NR
Strutchfield et
al. LA No Yes No NR Yes Yes
Strutchfield et
al. NH No Yes Yes NR Yes Yes
Bogdanovic et
al. SC Yes No Yes No Yes Yes
Bogdanovic et
al. MC No Yes Yes Yes Yes Yes
Redahan et al. 1A NR NR NR NR NR NR
Redahan et al. 1B NR NR NR NR NR NR
Redahan et al. 2A Yes NR Yes NR Yes NR
Redahan et al. 2B NR NR NR NR NR NR
This Report 304 Yes Yes Yes Yes Yes Yes
This Report 405 No Yes Yes Yes Yes Yes
This Report 404 No No Yes Yes Yes Yes
This Report 413* Yes Yes Yes Yes Yes Yes
Table containing the clinical presentation and residual clinical features on the family members affected by
immune complex mediated MPGN; * Index patient
51
Table 10: Immune mediated laboratory data
Author
Reference
Patient
Designation
Serum
Creatinine
umol/l
Serum
Albumin g/l Serum C3 Serum C4
Berry et al. WG 44 28 Normal Normal
Berry et al. KG 159 30 Normal Normal
Strutchfield
et al. LA 41 31 Normal NR
Strutchfield
et al. NH 40 24 Normal NR
Bogdanovic
et al. SC 35 13 Decreased Decreased
Bogdanovic
et al. MC 61 23 Normal Normal
Redahan et
al. 1A NR NR NR NR
Redahan et
al. 1B NR NR NR NR
Redahan et
al. 2A NR NR Decreased Decreased
Redahan et
al. 2B NR NR NR NR
This Report 304 238 16 Normal Normal
This Report 405 97 34 Normal Normal
This Report 404 71 14 Normal Normal
This Report 413* 39 26 Normal Normal
Mean 83 24
Median 53 25
Mode Not
Calculated
Not
Calculated
Standard
Deviation 66,61 7,39
Table containing the laboratory data on the family members affected by immune complex mediated MPGN; * Index patient
52
Table 11: ESRD and Inheritance Pattern
Author
Reference
Patient
Designation Age at ESRD (years) Inheritance Pattern
Berry et al. WG Not by follow up Multigenic/ X-linked
Berry et al. KG Not by follow up Multigenic/ X-linked
Strutchfield et
al. LA Not by follow up X-linked Recessive
Strutchfield et
al. NH 5 Demised X-linked Recessive
Bogdanovic et
al. SC Not by Follow Up Multigenic
Bogdanovic et
al. MC 8.5 Multigenic
Redahan et al. 1A 21 Autosomal Recessive
Redahan et al. 1B 21 Autosomal Recessive
Redahan et al. 2A 23 Autosomal Recessive/ X-
linked
Redahan et al. 2B 17 Autosomal Recessive/ X-
linked
This Report 304 Demised before ESRD
occurred Multigenic
This Report 405 19 Multigenic
This Report 404 Not by follow up Multigenic
This Report 413* Not by follow up Multigenic
Mean 20
Median 21
Mode 21
Standard
Deviation 2,28
Table containing the age at which end stage renal disease (ESRD) occurred in family members affected by immune complex mediated MPGN and the family inheritance patterns suggested by studies; * Index patient
53
The complement- mediated families consisted of sixteen family members, had a mean age
at diagnosis of fifteen years with a mean follow up period of six years (table 12). Almost
half of the family members in this group had a previous diagnosis of MPGN type III
compared to only one family member in the immune complex mediated group.
Most of the family members presented with hypertension and proteinuria (table 13) and
more family members had a decreased serum complement, 41% versus 14% in the immune
mediated group (table 14). There are marked variations in the serum creatinine results, due
to some family members presenting late or some had been previously diagnosed at other
hospitals and their results at diagnosis were not available, hence the large standard
deviation for the serum creatinine.
Only three patients had ESRD by the time the reports were written and their ages
fluctuated from 10 to 54 years, with a mean disease duration of twelve years. With regards
to the inheritance pattern, there again is a marked variance but autosomal dominance
occurs more frequently, however that is mainly due to the study by Neary et al. which had
six family members (table 15) of the total sixteen family members.
54
Table 12: Complement mediated demographics
Author
Reference
Patient
Designation Gender
Age at
Diagnosis
(years)
Follow up
(years)
Previous
MPGN
New
Classification
Berry et al. JM Male 10 5 3 CM
Berry et al. PM Female 9 2 1 CM
Bakkaloglu et
al. SG Male 3 1 1 CM
Bakkaloglu et
al. AG Male 10 7 1 CM
Bakkaloglu et
al. BG Male 3 6 1 CM
Bakkaloglu et
al. IG Male 10 1 1 CM
Bakkaloglu et
al. MY Male 9 4 1 CM
Bakkaloglu et
al. FY Male 13 2 1 CM
Motoyama et
al. Case 1 Female 14 1 1 CM
Motoyama et
al. Case 2 Female 9 31 1 CM
Neary et al. 213 Male 4 NR 3 CM
Neary et al. 105 Male 51 NR 3 CM
Neary et al. 212 Male 28 NR 3 CM
Neary et al. 214 Female 21 NR 3 CM
Neary et al. 103 Female 25 NR 3 CM
Neary et al. 223 Female 16 NR 3 CM
Mean
15 6
Median
10 3
Mode
10 2
Standard
Deviation 12,10 9,04
Table containing the demographics for the family members with complement mediated MPGN
CM: complement mediated MPGN; NR: Not recorded
55
Table 13: Complement mediated clinical presentation
Author
Reference
Patient
Designation Hypertension
Residual
Hypertension Haematuria
Persistant
Haematuria Proteinuria
Persistant
Proteinuria
Berry et al. JM Yes NR Yes Yes Yes NR
Berry et al. PM Yes NR Yes Yes Yes NR
Bakkaloglu et
al. SG Yes NR NR NR Yes NR
Bakkaloglu et
al. AG Yes NR NR NR Yes NR
Bakkaloglu et
al. BG No Yes NR NR Yes No
Bakkaloglu et
al. IG No Yes NR NR Yes No
Bakkaloglu et
al. MY Yes Yes NR NR Yes Yes
Bakkaloglu et
al. FY Yes No NR NR Yes No
Motoyama et al. Case 1 No No Yes Yes Yes No
Motoyama et al. Case 2 Yes No Yes No Yes Yes
Neary et al. 213 Yes NR No NR Yes Yes
Neary et al. 105 Yes NR Yes NR Yes Yes
Neary et al. 212 Yes NR Yes NR Yes NR
Neary et al. 214 No NR Yes NR Yes NR
Neary et al. 103 Yes NR NR NR Yes NR
Neary et al. 223 Yes NR Yes NR Yes NR
Table containing the clinical presentation and residual clinical features on the family members affected by
complement mediated MPGN
56
Table 14: Complement mediated laboratory data
Author Reference Patient
Designation
Serum
Creatinine
umol/l
Serum
Albumin g/l Serum C3 Serum C4
Berry et al. JM 26 18 Decreased NR
Berry et al. PM 247 15 Decreased NR
Bakkaloglu et al. SG 22 Normal Normal Demised
Bakkaloglu et al. AG 25 Normal Normal CRF
Bakkaloglu et al. BG 25 Normal Normal NR
Bakkaloglu et al. IG 24 Normal Normal NR
Bakkaloglu et al. MY 795 26 Decreased Decreased
Bakkaloglu et al. FY 176 24 Decreased Decreased
Motoyama et al. Case 1 62 45 Decreased Normal
Motoyama et al. Case 2 62 29 Decreased Decreased
Neary et al. 213 NR 21 Decreased Normal
Neary et al. 105 133 33 Normal Normal
Neary et al. 212 NR 26 Normal Normal
Neary et al. 214 NR 28 Normal Normal
Neary et al. 103 NR 30 Normal Normal
Neary et al. 223 NR 40 Normal Normal
Mean
175 27
Median
62 26
Mode
53 26
Standard Deviation 221,78 7,56
Table containing the laboratory data on the family members affected by complement
mediated MPGN. NR: Not Recorded
57
Table 15: Complement mediated age of ESRD and inheritance patterns
Author
Reference
Patient
Designation Age at ESRD Inheritance Pattern
Berry et al. JM Not by follow
up Multigenic
Berry et al. PM Not by follow
up Multigenic
Bakkaloglu
et al. SG NR
Autosomal Dominant/ X-linked with incomplete
penetrance
Bakkaloglu
et al. AG 10
Autosomal Dominant/ X-linked with incomplete
penetrance
Bakkaloglu
et al. BG NR
Autosomal Dominant/ X-linked with incomplete
penetrance
Bakkaloglu
et al. IG NR
Autosomal Dominant/ X-linked with incomplete
penetrance
Bakkaloglu
et al. MY NR
Autosomal Dominant/ X-linked with incomplete
penetrance
Bakkaloglu
et al. FY NR
Autosomal Dominant/ X-linked with incomplete
penetrance
Motoyama et
al. Case 1 NR Unclear
Motoyama et
al. Case 2 NR Unclear
Neary et al. 213 10 Autosomal Dominant
Neary et al. 105 Not by follow
up Autosomal Dominant
Neary et al. 212 Not by follow
up Autosomal Dominant
Neary et al. 214 Not by follow
up Autosomal Dominant
Neary et al. 103 54 Autosomal Dominant
Neary et al. 223 Not by follow
up Autosomal Dominant
Table containing the age at which end stage renal disease (ESRD) occurred in family members
affected by complement mediated MPGN and the family inheritance patterns suggested by studies.
NR: Not Recorded
58
DISCUSSION
59
Redahan et al suggested that complement dysregulation played an important “role in the
pathogenesis of immune complex mediated MPGN” as evidenced by the following (16) :
Familial cases of type II MPGN have been found to have mutations in complement
factors and in complement factor proteins resulting in dysregulation of the
complement cascade resulting in disease. (16)
The study by Neary et al found a link between chromosome 1q, a locus containing
multiple genes for factors affecting the complement cascade. (4)
A previous cohort of MPGN type I patients with both immunoglobulins and
complement staining on IFM were found to have mutations in complement factor
H (10, 4%) and complement factor I (6, 2%), suggesting dysregulation of the
alternative pathway of the complement cascade. (19)
This however does not explain why certain family members are affected, particularly in
families with consanguineous marriages. Nor does it account for the other 83, 6% of
people with MPGN type I. The study by Servais et al. also did not look into the underlying
cause of MPGN (19) was it caused by autoimmune diseases and of those diseases, which
ones are affected by abnormal alternative pathway of complement? Thus, do those results
apply to familial MPGN? While the above is useful in giving possible genes to look at in
the future, more work needs to be done in this field.
By doing the systematic review, it is clear that there are two forms of familial MPGN,
namely the complement mediated and the immune complex mediated MPGN. Therefore,
the current classification of MPGN needs to change and a fourth category added to the
immune complex mediat